Green Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/greenchem Page 1 of 7 Green Chemistry Green Chemistry Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Oxyhalogenation of thiols and disulfides into sulfonyl chlorides/bromides using oxone-KX(X= Cl or Br) in water Sridhar Madabhushi,*a Raveendra Jillella,a Vinodkumar Sriramoju a and Rajpal Singh b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x A simple and rapid method for efficient synthesis of sulfonyl in water medium. Application of water as a reaction medium chlorides/bromides by oxyhalogenation of thiols and also has several other advantages. For example, it enables more disulfides with oxone-KX( X=Cl or Br) using water as the control on exothermic reactions due to its high specific heat solvent is described. 50 capacity. In a biphasic reaction system, organic products can be easily isolated by phase separation or by simple filtration. Water, 10 Introduction with its dense network of hydrogen bonds, can highly influence the reactivity of a substrate. Water has high dielectric constant Manuscript Organic sulfonyl chlorides are highly important as protecting and low molecular size and hence, it can dissolve polar and ionic agents in organic synthesis 1 and they are also useful precursors 55 compounds such as salts, surfactants and cyclodextrins etc., very for preparation of sulfonic acids, sulfonamides and sulfonates. In addition, they are industrial important building blocks for efficiently. For this reason, water is often used as a co-solvent for 15 manufacture of elastomers, pharmaceuticals, dyes, detergents, ion carrying out reactions between a organic substrate and a reactive exchange resins, herbicides etc. 2 Sulfonyl chlorides are generally inorganic salt such as peroxysulfates, permanganates, perhalates, prepared by oxychlorination of thiols and disulphides using nitrates etc. 3 aqueous chlorine. Many methods are available in literature to accomplished this reaction using a variety of reagents such as 60 Results and Discussion 4 5 6 7 20 SOCl 2-H2O2, POCl 3-H2O2, TiCl 4-H2O2, and Me 3SiCl-KNO 3. Accepted The other important approaches for preparation of sulfonyl Oxone or potassium peroxymonosulfate chlorides include chlorination of sulfonic acid is using reagents 8 [2KHSO 5·KHSO 4·K 2SO 4] is an inexpensive, environmentally such as 2,4,6-trichloro-1,3,5-triazine , thionylchloride , trichlroacetonitrile-triphenylphosphene 9 and reaction of Grignard benign and widely used stable oxidant. It has been extensively 10 25 reagents with sulfur dioxide and thionyl chloride. In most of studied in literature for a variety of oxidative transformation and these methods, toxic and highly corrosive reagents were used and 65 some the important reactions are oxidation of alkenes to reaction was carried out using organic solvents. These methods epoxides, 12 thioethers to sulfones, 13 aldehydes to carboxylic also suffer with one or more disadvantages such as vigorous acids, 14 tertiary amines to amine oxides 15 etc. It is also shown to reaction conditions, formation of side products, long reaction 16 be useful for promoting aromatic bromination, 30 times and tedious workup procedures for isolation of the pure products. Therefore, development of a milder and practical method for the synthesis of sulfonyl chlorides is highly desirable. Growing usage of volatile organic solvents in industry has Chemistry become a major environmental concern, and in recent years, 35 studies on development of ‘green’ process by replacing toxic- organic solvents with alternative non-toxic media have gained high importance. 11 Water is a non-flammable, non-toxic, inexpensive, abundantly available solvent. In literature, many organic transformations were known to proceed very efficiently Green a 40 Fluoroorganics Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India; email: [email protected]; Ph. +91 40 27191772, Fax: +91 40 b 27160387. Centre for Fire Explosives and Environmental Safety, 70 17 18 DRDO, Timarpur, New Delhi-110054, India. hydroxybromination, and benzylic oxidation reactions in the presence of salts such as NH 4Br, KBr etc. Recently we found 45 Electronic supplementary information: Characterization data and that alkynes undergo efficient oxyhalogenation with oxone -KX 19 copies of NMR spectra (X=Cl, Br or I) and convert into α,α-dihaloketones. In This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 Green Chemistry Page 2 of 7 continuation of our research interest on oxone mediated 35 the other oxidants, i.e. H 2O2, mCPBA and TBHP under the oxyhalogenation reactions, we herein report a new application of reaction conditions. oxone-KX(X=Cl or Br) for efficient preparation of sulfonyl chlorides (68-98%) and sulfonyl bromides (89-96%) from thiols 5 and disulfides by oxyhalogenation reaction under mild conditions using water as a reaction medium as shown in Scheme 1. In our preliminary experiments, reaction of thiophenol with 0.5 equivalent of oxone and 0.5 equivalent of KCl in water at room temperature was found to produce diphenyl disulfide in 10 quantitative yield. However, when 1.0 equivalent of oxone and 1.0 equivalent of KCl were used in this reaction, we obtained a mixture of diphenyl disulfide and sulfonyl chloride and with 2.5 equivalent of oxone and 1.0 equivalent of KCl, we obtained phenylsulfonyl chloride in 98% yield. In our study, oxone was 15 found to promote this reaction effectively also with other halogen sources such as aq. HCl, NaCl, KBr, KI, aq. HBr, AlCl 3, FeCl 3, ZnCl 2 and NH 4Br, which gave benzenesulfonyl halide in 88-98% yields in 10-20 minutes. These results are shown in Table 1. Manuscript Accepted 20 Chemistry Here, though we could prepare phenyl sulfonyl iodide in high yield (90%) by this method using oxone-KI, it was found to be highly unstable and decomposed rapidly at room temperature. 25 We also studied the scope of oxyhalogenation of a thiol with other oxidants such as 2-iodoxybenzoic acid (IBX), sodium Green periodate, hydrogen peroxide, m-chloroperbenzoic acid(mCPBA) and t-butyl hydrogenperoxide(TBHP). For example, results observed in the reaction of thiophenol with these oxidants in the 30 presence of KCl at room temperature using water as the solvent are shown in Table 2. In this study, IBX was found to produce a mixture of disulphenyl disulfide and phenyl sulfonyl chloride 2:1 ratio and with sodium periodate, we obtained only diphenyl disulfide in quantitative yield and no reaction was observed with 40 2 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 3 of 7 Green Chemistry In the study of screening of halogen sources (Table 1), we and 1.0 equivalent of KX and it is in accordance with the found formation of sulfonyl chlorides and bromides in maximum 40 proposed mechanism. yields with KCl and KBr respectively. Next, we studied oxychlorination of a variety of aliphatic, aromatic and 5 heteroaromatic thiols 1a-n with oxone-KCl in water and obtained corresponding sulfonyl chlorides 2a-n in 68-95% yields as shown in Tables 3. Using a similar procedure, we studied oxybromination of thiols 1a-f with oxone-KBr and observed formation of corresponding sulfonyl bromies 3a-f in 89-96% 10 yields as shown in table 4. Manuscript Accepted 15 chloride and at the end of reaction, no disulfide was observed and only sulfonyl chloride formed.. In a control experiment, reaction of thiophenol with 0.5 equivalent of oxone and 0.5 equivalent of KCl gave diphenyl disulfide in 96% yield in 10 min. It shows that oxone-KCl initially oxidizes thiol into disulfide, which 20 undergoes further reaction and converts into sulfonyl chloride. We prepared a variety of symmetrical disulfides, which were found to undergo efficient oxyhalogenation with 2 equivalents of oxone and 2 equivalents of KCl in water at room temperature producing sulfonyl chlorides in 82-98% yields as shown Table 5. Chemistry 25 45 The plausible mechanism for transformation of thiols into sulfonyl halides via disulfides by reaction with oxone –KX is Conclusions shown in Scheme 2. In this mechanism, oxone initially reacts with KX in water and produces hypohalous acid(HOX).20 Next, In conclusion, we showed an efficient and rapid method for 30 hypohalous acid reacts with thiol to produce sulfinyl halide, preparation of sulfonyl chlorides and bromides in high yields by Green which converts into a disulfide by reaction with another molecule oxyhalogenation of thiols and disulfides with oxone-KX(X=Cl of thiophenol. In the subsequent steps, disulfide reacts with HOX 50 or Br) under mild conditions using water as a solvent. and converts into RS(O)-S(O)R. It is amply reported in literature 21 General Information that RS(O)-S(O)R rapidly rearranges into RSO 2-SR, which 35 upon reaction with HCl cleaves into RSO 2X and RSH.